A Lot of Nerve

The War of the Soups and the Sparks: The Discovery of
Neurotransmitters and the Dispute over How Nerves
Communicate. Eliot Valenstein. xviii + 237 pp. Columbia
University Press, 2005. $31.

Scientific style and personality loom large in Nerve
Endings and The War of the Soups and the Sparks, two
new books documenting discoveries about the neuron's anatomical
structure and its modes of transmitting nerve impulses. These
volumes tell a story that begins in the late 19th century and is
still being written today. Both accounts meld individual biographies
of scientists with descriptions of experimental procedures and raise
questions about the ways in which styles of research, creativity and
intuition have contributed to the practice of experimental neuroscience.

In Nerve Endings, Richard Rapport, a neurosurgeon by
training, focuses on the life and work of the Spanish artist and
scientist Santiago Ramón y Cajal and to a lesser extent on
Cajal's Italian rival, Camillo Golgi. Cajal's late 19th-century
conception of a discrete nervous cell, separated from other cells by
a gap (later called a synapse), came to replace the older reticular
theory, which postulated that nervous tissue comprised a seamless,
continuous web—an unbroken network, or
reticulum—through which nerve impulses could travel
in any direction. Golgi's adamant advocacy of the reticular theory
was the source of his conflict with Cajal.

Golgi, after attending medical school, began his scientific career
in experimental pathology by joining the even younger histologist
Giulio Bizzozero, who was doing original research at the University
of Pavia. In 1872, at age 28, Golgi left the university and, to
support himself, took a job as chief physician at a mental hospital
near Pavia. In his spare time, working in the kitchen of his
hospital apartment, he strove to find a stain for neural tissue that
could more clearly isolate neural structures. The following year he
achieved what he termed the black reaction by using a
silver nitrate stain that affected only a small percentage of
neurons, allowing him to trace nerve structures more precisely than
had been done before. He was then able to detect branching of axons
(now understood to be the single fibers that conduct impulses away
from the cell body) and to confirm the existence of protoplasmic
extensions, or dendrites (now known to be the fibers on a cell body
that receive signals sent from the axons of other cells). However,
he was convinced that dendrites did not actually participate in
neural transmission but instead merely played a supportive role in
the network. His silver nitrate stain was nonetheless a formidable
advance and was in widespread use by the 1880s. For his
accomplishments, Golgi accepted a chair in histology at the
University of Pavia.

Cajal, who was nine years younger than Golgi, took to drawing,
watercolors and photography as a young boy. Eventually he turned
toward anatomical studies, employing his artistic skills for medical
illustration. After his medical training at the University of
Zaragoza, he taught histology, and in 1887 he began experimenting
with the Golgi stain in his own kitchen laboratory. Cajal pioneered
an improved method that he referred to as the double impregnation
procedure. It involved soaking embryonic nerve tissue and cerebellar
tissue first in fixative and then in silver nitrate, and then
repeating this process. This method provided a deeper stain of nerve
tissue, allowing Cajal to visually track the paths of axons and map
the structure of neuronal cell bodies in greater detail. He found
that axons ended in gray matter, meaning that the bulges (boutons)
on the ends of axons conformed to patterns of dendrites on nearby
cells. Most strikingly, he noted that the ends of axons were not
seamlessly connected to other neurons but were separated from them
by a gap. He also proposed a theory of dynamic polarization, in
which nerve impulses were transmitted in one direction only, from
the neuron's dendrites to the axon.

Cajal made many artistic renderings of his observations, some of
which are helpfully reprinted in this volume. As Rapport reminds us,
however, the gaps between neurons were not actually visible to
Cajal, and it was only 50 years later with the aid of an electron
microscope that they could be directly seen. How then did Cajal
intuit such gaps? Rapport suggests that Cajal, because he was
relatively isolated from the scientific mainstream and was not
wedded to the reticular theory, did not have preconceived notions of
what he might find. He used his imaginative capacity to see what
others could not.

Nonetheless, the validity of Cajal's findings was not so easily
apparent to others. He resorted to creating his own journal to
publish his results, but his writings in Spanish attracted little
attention. He therefore translated his work into French (which was
considered a more acceptable language for reporting scientific
findings) and submitted it to prominent German journals. As Rapport
tells it, acceptance of the neuron theory began when the renowned
histologist Albert von Kölliker was converted from the
reticularist position at an 1889 Anatomical Society meeting in
Berlin. Yet Golgi still adamantly opposed the neuron theory, a
rejection that Rapport suggests may have been due to Golgi's rigid
personal style. Indeed, even in 1906, by which time the theory had
become widely accepted, Golgi attacked it in the speech he gave when
he and Cajal were awarded the Nobel Prize.

Influenced by the work of Pierre Flourens, Golgi was a staunch
holist with regard to brain function, a position that may have
contributed to his opposition to the existence of discrete cell
entities and one-way transmission in the brain. Yet, aside from
mentioning the work of Karl Dieters and Joseph von Gerlach, Rapport
does not give much attention to the assumptions and findings of the
reticularists. He points out the prevalence of their views in
various scientific circles of the time but does not elaborate on the
stakes of their debates with the neuronists. One also wonders how
those debates might have intersected with the drive in Germany and
France, beginning in the 1870s, to localize brain function to
certain areas of the cortex. Rapport's narrative focuses instead on
the personal dynamics between Cajal and Golgi, leaving broader
aspects of the debate out of view. Cajal emerges as the clear hero
as Rapport tells it: Not only was he right, but he was also more
keenly observant, more creative and more psychologically balanced
than Golgi.

Three decades after Cajal intuited gaps between neurons, the German
pharmacologist Otto Loewi had another creative neuroscientific
insight, one that came to him in a dream. As Eliot Valenstein
recounts in The War of the Soups and the Sparks, this dream
(which recurred two nights in succession in 1921) gave Loewi the
inspiration for an experiment that he conducted using two frog
hearts to demonstrate that the vagus nerve produced its effect on
the heart by secreting chemical substances. Merely performing this
crucial test was not sufficient proof of chemical transmission,
however, and it took Loewi a decade to carry out a decisive series
of experiments to satisfy his critics.

Valenstein, an emeritus professor of neuroscience and psychology at
the University of Michigan, uses the example of the dream to
characterize Loewi's scientific style as speculative and bold, in
direct contrast to that of the British pharmacologist Henry Dale.
Years earlier Dale had begun research on the effects of ergot
extracts on biological functions and had found amine substances that
could mimic the actions of sympathetic or parasympathetic nerves.
Yet in 1914, when Dale performed his experiments, amine substances
such as noradrenaline and acetylcholine were not understood to be
present in the body. As Valenstein points out, Dale never made the
theoretical leap to imagine that such a chemical could be emitted by
the nerves themselves. Despite the stylistic differences between
these two scientists, it was their combined experimental work that
led to the finding of neurohumoral secretion of the nerves, a
discovery that earned them the Nobel Prize in 1936.

The idea that chemicals were the conduit between neurons was not a
popular one, however—especially among neurophysiologists, who
thought this mode of transmission would be too slow. In a short but
important chapter, Valenstein uncovers the professional differences
between neurophysiologists and pharmacologists, noting how these
differences played a role in the war between "the soups and the
sparks"—between those who argued for chemical
transmission and those who supported electrical transmission.
Neurophysiologists saw themselves as practicing an elevated
discipline, and they looked down on pharmacological work as labor
carried out with "spit, sweat, snot, and urine."

The tension between these very different disciplines, which receives
only limited attention in this book, formed an important reason for
the slow acceptance of a neurohumoral theory of transmission.
Valenstein does discuss the views of the prominent neurophysiologist
John Eccles, but the sparks side of the "soups and sparks"
debate takes a backseat to the careers and life stories of Loewi,
Dale and Walter Cannon, the pioneers of the neurohumoral theory.

Even after neurohumoral transmission had been established for nerve
stimulation of various organs such as the heart, there was still a
good deal of hesitation to ascribe similar mechanisms of
transmission to the brain. By the 1950s, a number of different
monoamines, such as adrenaline and serotonin, had been found in the
brain, and the electron microscope revealed vesicles in the axon
that looked like possible containers for neurotransmitters. Despite
such findings, however, few drew the conclusion that brain synapses
were crossed by chemicals. It would take another decade to track
neurotransmitter action across brain synapses and for neurohumoral
secretion in the brain to become accepted. It remains puzzling why
such findings were so slow in coming, a point Valenstein underscores
but does not fully explain.

These two books solidly document the personal and professional lives
of scientific "winners." Yet it is important to heed the
final cautionary notes of the respective authors: Even as chemical
transmission has now been established as the rule in neuronal
communication, there are a small number of instances (in the retina,
for example) in which neurons communicate directly through
electrical transmission, without a gap but with protoplasm stretched
between neuronal membranes, the so-called gap junction. Stories,
then, of overcoming outdated assumptions, when viewed over the
course of time and further research, can sometimes demonstrate that
the losers were partially right, their views becoming a special case
rather than the general one.

One drawback of histories such as these, which sharply focus on the
heroic successes in neuroscience, is that they obscure the rationale
and stakes for the different scientific viewpoints held at the time.
That said, however, these books are, in the end, aimed less at
charting the contours of broad scientific debate than at documenting
creative leaps in the process of scientific discovery.